The effect of dexmedetomidine on emergence delirium of postanesthesia events in pediatric department: A systematic review and meta-analysis of randomized controlled trials

Background: Emergence delirium (ED) is a common occurrence in pediatric postanesthesia events, leading to negative outcomes. Dexmedetomidine (DEX), as an anesthesia adjuvant, has shown promise in preventing ED in adult surgeries, and it has been increasingly used in pediatric surgical settings. However, its effectiveness in other postanesthesia events, such as MRI examinations and ambulatory surgery centers, remains unclear. This meta-analysis aims to assess the safety and efficacy of DEX in preventing ED in various pediatric postanesthesia events beyond surgery. Methods: Prospective randomized controlled trials were searched in Pubmed, Web of Science, and EBSCO until October 13, 2023. Comparisons were made between DEX and other sedatives or analgesics in different postanesthesia events (including surgery operations, the examination of MRI, day surgery, and invasive action). Subgroup analyses were conducted based on drug delivery methods, medication timing, DEX dosages, use of analgesics, event types, and recovery time. Results: A total of 33 trials involving 3395 patients were included. DEX significantly reduced the incidence of ED (odds ratios [OR] = 0.23, 95% confidence interval [CI]: 0.19–0.27, I2 = 37%, P < .00001). Intranasal delivery of DEX was the most effective (OR 0.18, 95% CI: 0.10–0.32, P < .00001, I2 = 0%). DEX also showed benefits in day surgery and mask insertion events (OR 0.30, 95% CI: 0.14–0.26, P = .001, I2 = 0%). Conclusion: DEX demonstrates superior efficacy in preventing ED in pediatric postanesthesia events compared to other sedatives and analgesics. Its use is recommended in various settings for its safety and effectiveness in managing ED.


Introduction
Delirium, a disorder of neurocognition characterized by alterations in attention and awareness [1] is prevalent in pediatric patients, especially in hospitalized children, leading to serious outcomes. [2]Emergence delirium (ED) is a form of psychomotor agitation and delirium that typically occurs about 45 minutes after anesthesia. [3]Given the unique characteristics of children, the use of anesthetics is necessary during certain events in pediatric diagnosis and treatment, resulting in a high incidence of ED ranging from 10% to 80%. [4]ED can lead to negative effects such as self-injury, prolonged recovery time, and dissatisfaction among parents and caregivers. [5]exmedetomidine (DEX), a selective α-2 agonist, has been shown to prevent ED by exhibiting anxiolytic, analgesic, and sedative properties. [6]Despite not being officially approved for pediatric use in any guidelines, DEX is widely used to prevent ED in various pediatric events. [7]Compared to other sedative drugs, DEX has less impact on the nervous system, reduces the need for opioids and anesthetics, [6] and is popular for managing postoperative complications in pediatric departments.
However, the application of DEX is limited in nonsurgical anesthesia procedures in pediatric diagnoses and treatments, such as day case surgeries, MRI examinations, and invasive catheterizations, due to factors like dosage, timing, and effectiveness.This systematic review and meta-analysis aim to evaluate the impact of DEX as an anesthesia adjuvant on ED in pediatric patients and to discuss any potential limitations.

Materials and methods
We searched the databases including "Pubmed," "Web of Science," and "EBSCO" of all resources through the PICOS (Population, Intervention, Comparison, Outcome, Study design) method until 13th October 2023.The entry words included "child" OR "children" OR "pediatric" AND "dexmedetomidine" OR "precedex" OR "MPV-1440" OR "MPV 1440" OR "Dexmedetomidine Hydrochloride" OR "Hydrochloride, Dexmedetomidine" AND "delirium" OR "Subacute Delirium" OR" Delirium, Subacute" OR" Deliriums, Subacute" OR" Subacute Deliriums" OR" Delirium of Mixed Origin" OR" Mixed Origin Delirium" OR" Mixed Origin Deliriums" AND "trails" and the search scope was "all fields."Because all studies about the effect of DEX versus other drugs (placebo or other sedatives) on delirium in pediatric patients were eligible in this meta-analysis, we did not confine the search words of control drugs and study design, even nondrug.The inclusion criteria included the following: (1) participants with age <18 years; (2) management with prophylactic or therapeutic DEX and placebo or other sedatives or non-drug; (3) well-defined indicators associated with ED or comparisons of potential symptoms associated with the use of DEX; (4) randomized controlled trial.The exclusion criteria included the following: (1) participants with age ≥18 years; (2) management with DEX alone; (3) review or meta-analysis; (4) retrospective articles; (5) basic research; (6) article published as an abstract, letter, case report, editorial, note, method, or protocol; (7) article presented in non-English language.
Agitation is an unpleasant state of extreme arousal while delirium is a disturbance of consciousness and cognition. [8]fter discussion, we finally quit these articles because the conceptions of agitation and delirium are different.However, we preserve some articles of agitation for using Pediatric Anesthesia Emergence Delirium (PAED) scale to assess the eventual outcomes, because to date, the only validated scale is the PAED. [5]esides, some articles have no certain conclusion or the opposite result of anticipation about the effect of DEX and other sedatives.We also accept them aiming to analyze the possible causes of non-results for more comprehensive demonstration of DEX.
It is also important to note that due to the limited number of relevant surgical articles that met our criteria, the metaanalysis primarily focuses on the discussion of dexmedetomidine in preventing emergence delirium during short-term anesthesia in pediatric patients.

Data analysis
This meta-analysis aimed to analyze whether DEX had an advantage in reducing the incidence of ED of post-event in pediatric patients when compared with placebo or other sedatives or non-drug and the lack it may exist.
Two authors were independently responsible for reviewing the titles, abstracts, or both and summarized the data of the included literature.Another author was in charge of the data discrepancy adjustment.
Two authors were responsible for extracting the following information: (1)  Two authors independently assessed the quality of the included trials.The risk of bias of randomized controlled trials (RCTs) was assessed by the Cochrane Collaboration Risk of Bias Assessment tool including 7 items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and others (bias due to vested financial interest and academic bias).If a trial had one or more of the items to be judged as high or unclear risk of bias, this trial was classified as having high risk. [9]If the 2 authors had different assessment results, they will be consulted by the third or the fourth one.Eventually, the authors reached a consensus.All included trials were grouped based on different control drugs.
RevMan Review Manager version 5.4 (Cochrane Collaboration, Oxford, UK) was used to perform statistical analyses.The values of I 2 and the Mantel-Haenszel chi square test (P-value for heterogeneity) were used to evaluate the heterogeneity of included studies.And the values of I 2 < 40%, 40 to 60%, and >60% represented low, moderate, and high heterogeneity, respectively. [10]If I 2 > 50% or a P-value for heterogeneity <0.1 was identified, the method of random-effect model analysis was applied to analyze the data.Conversely, if I 2 < 50% or a P-value for heterogeneity .1 was presented, the method of a fixed-effect model was used. [11]The dichotomous outcome was reported as odds ratios (OR) with 95% confidence interval (CI).The statistical tests were two-sided, and a P-value for overall effect <.05 was considered to have a significant difference.
Sensitivity analysis was conducted to solve the problem of significant heterogeneity (I 2 > 20%) through the method of subgroup analysis or one-by-one literature removal.Metaregression was used to investigate the heterogeneity sources for the group with I 2 > 20% according to possible risk factors.A subgroup analysis proceeded based on the risk factor with P < .05by meta-regression analysis; conversely, the method of one-by-one literature removal was used if P-values of all risk factors were .05or more.

Bias risk assessment
Bias risk of 33 RCTs was assessed by the Cochrane Collaboration Risk of Bias Assessment tool.Random sequence generation was assessed as a low risk of bias in 32 studies (97%), allocation concealment was assessed in 28 studies (85%), blinding of participants was assessed in 30 studies (91%), blinding of outcome assessment was assessed in 28 studies (85%), incomplete outcome data were assessed in 31 studies (94%), and selective outcome reporting was assessed in 32 studies (97%).Twenty four RCTs [13,14,16-19,21,23- 25,27,28,30,31,33,34,36-42,44] were assessed to be of high quality (see Fig. 2 and Figure S1, Supplemental Digital Content, http:// links.lww.com/MD/N387 which illustrates the risk of bias graph review authors judgments about each risk of bias item presented as percentages across all included studies).

Subgroups analysis
To further search the effects of DEX on ED incidence, we conducted the subgroup analysis in 5 parts: ways of drug delivery (oral, intravenous, and intranasal), medication time (premedication, during the event, and before the event finishing), the different dosages of DEX (low dose [<0.5 μg/kg], moderate dose [0.5-1 μg/kg], high dose [>1 μg/kg], continuous dosage, and both of bolus and continuous dosage), with or not analgesic (with one analgesic, with 2 analgesics, with 3 analgesics, and with no analgesic), and type of event (surgery, MRI, and other events).The outcomes of subgroup analysis are displayed in Table 3.

Way of drug delivery
Our research discussed that DEX effectively decreased the incidence of ED in the intravenous way (OR 0.21, 95% CI: 0.14-0.30,P < .00001,I 2 = 52%), intranasal way (OR 0.18, 95% CI: 0.10-0.32,P < .00001,I 2 = 0%), and oral way (OR 0.25, 95% CI: 0.08-0.75,P = .01,I 2 = 0%).The most effective route may be the intranasal way (see Figure S9, Supplemental Digital Content, http://links.lww.com/MD/N387 which illustrates the comparison of pediatric ED between dexmedetomidine and all comparator groups [subgroup of different ways of drug delivery]).This way is simple to act and suitable for those children who are out of control.

Medication time
When adding the subgroup of medication time, we found except post-event (OR 0.

Type of event
Another subgroup analysis was according to the type of event.

Secondary outcomes
For investigating the comprehensive effects of DEX on patients in pediatrics, we tried to find the differences between DEX and other comparator groups on sedation effect before the events and the differences in recovery time after the events.Unfortunately, we could not explore any evidence or data about the effects before the events, but we found some data covering the recovery time after the events finished.And the outcomes are shown in Table 3.
Compared to other comparator groups, we found that DEX delayed the recovery time of children.

Discussion
The results of this meta-analysis suggested that DEX has more significant advantages in preventing ED in pediatric patients undergoing anesthesia compared to other methods, particularly in surgical settings.In the past, short-acting sedatives such as propofol, midazolam, and ketamine were commonly used in  pediatric clinics.Ketamine, an N-methyl D-aspartate antagonist, exerts sedative effects by inhibiting glutamate from binding to the N-methyl D-aspartate receptor.Because ketamine interacts with central nervous system receptors, including μ, κ, and δ opioid receptors, it also possesses analgesic properties. [45]owever, ketamine can lead to postoperative psychomimetic effects like ED, which are dose-dependent.On the other hand, alpha-2 adrenoceptor agonists like DEX can prevent these reactions. [46]Midazolam, a benzodiazepine, acts as a gammaaminobutyric acid agonist and is widely used for its anxiolytic effects [47] but has been associated with delirium at higher doses. [48]Propofol functions by enhancing the neuro-inhibitory activity of gamma-aminobutyric acid.Its rapid onset of action and short half-life facilitate a faster awakening once the infusion is discontinued.Unfortunately, propofol is associated with several unavoidable adverse effects.The most common is pain at the injection site.Additionally, airway obstruction and apnea are significant concerns that cannot be ignored.Other adverse effects include bradycardia, hypotension, and central nervous system excitation, which can potentially trigger seizures, among others. [49]Moreover, neither midazolam nor propofol provides analgesic effects.
Our data clearly demonstrated that DEX has significant benefits in preventing ED, a common and challenging complication in pediatric medical procedures. [3]ED not only increases the likelihood of additional complications, such as self-injury and prolonged recovery times but also impacts the satisfaction levels of both parents and caregivers. [9]Numerous factors contribute to the onset of ED, including the use of fast-acting volatile anesthetics, patient age, gender, surgical stimuli, postoperative pain, and anxiety due to separation from parents. [50]Primarily, there is an increase in cytokines, notably IL-6 and TNF-alpha, which lead to the development of neuroinflammation. [51][54] DEX is particularly effective because it readily crosses the blood-brain barrier [55] and has been proven   to reduce IL-6 cytokine levels in patients who undergo total intravenous anesthesia. [56]Additionally, DEX has been shown to lower levels of cortisol, C-reactive protein, TNF-alpha, and other interleukins such as IL-1β both 1 hour and 24 hours post-surgery. [57]Moreover, DEX enhances neuroinflammatory behavior by suppressing inflammatory mediators, controlling apoptotic signaling pathways, and reducing the generation of oxygen-free radicals. [58]In conclusion, DEX plays a crucial role in protecting the brain during episodes of delirium, highlighting its importance in pediatric anesthetic practice.As previously noted, postoperative pain is a significant factor contributing to ED. DEX serves not only as an analgesic but also reduces the required dosage of opioids.Studies indicate that DEX lessens perioperative pain and the need for analgesics, while significantly extending the duration of analgesia during the first 24 hours. [7]Aydogan, in his study, compared opioid dosages between patients administered DEX and those given midazolam. [38]The findings revealed that the DEX group required a lower dose of opioids than the midazolam group.Consequently, DEX can decrease both the risk and potential addiction associated with opioid use.This is particularly important considering that children, especially neonates, are believed to have immature metabolic systems. [59]DEX is advantageous in terms of safety due to its short elimination half-life; it is rapidly transformed into inactive metabolites through hepatic biotransformation. [7]urthermore, DEX minimally impacts the respiratory system and has been shown to reduce the incidence of postoperative nausea and vomiting. [7]However, it is not without side effects, which include hypertension, hypotension, and bradycardia, among others. [6]All the studies we reviewed acknowledged these issues but indicated that these symptoms are manageable and do not necessitate the use of any antagonists.
Although some literature indicated that DEX was less effective than propofol in preventing ED during MRI examinations, this is due to the use of suboptimal doses of DEX.Such literatures were excluded during sensitivity analysis.For example, Fang stated in his meta-analysis that propofol is preferable to DEX for MRI procedures, citing better outcomes in terms of recovery time and prevention of ED. [60] Bong noted in his study that not only did the propofol group outperform the DEX group, but even the saline group achieved more favorable results than those receiving DEX.It is important to note that in their researches, the dosage of DEX was 0.3 μg/kg, administered without any sedatives other than sevoflurane, [20] which has been linked to an increased risk of ED. [3] In Xu's article, a comparison was made between DEX and ketamine, both administered alongside a continuous infusion of propofol.The conclusion drawn was that ketamine and DEX had similar effects in preventing ED.However, due to the sedative effects of propofol, it is challenging to effectively distinguish between the impacts of ketamine and DEX on preventing ED.Moreover, the dosage of DEX was 0.3 μg/kg, which is considerably insufficient without other sedatives. [32]Considering the slower onset of action of DEX, [61] with a dose of 1 μg/kg taking effect after 45 minutes, [55] a loading dose is generally administered before events when using DEX.In children and adolescents, the recommended loading doses range from 0.5 to 2 μg/kg administered over 10 minutes, followed by a recommended maintenance dose of 0.5 to 1 μg/kg/h.The dosage should be reduced when used in preterm neonates or neonates. [62]n our meta-analysis, a low dose (<0.5 μg/kg) emerged as the better choice for preventing ED when administered in a single bolus.However, the most effective method appeared to be the use of a continuous dose throughout the procedure.Nonetheless, it is important to note that in the reviewed articles, there was always the concurrent use of at least 1 sedative or analgesic alongside DEX.These sedatives and analgesics typically have a synergistic effect with DEX, which can lead to an unclear understanding of a safe dose.Although Manning suggests in his article that 0.5 μg/kg may be the appropriate dose to prevent ED and that exceeding this dose does not provide additional protection, [50] Mantecón-Fernández indicates that the effective continuous dose ranges from 0.1 to 2 μg/kg/h. [59]However, the dosages of other sedatives used concurrently were not discussed in these studies.Therefore, given the existing uncertainties in diagnosis and treatment, ongoing research is essential to determine the optimal dosages of DEX and other medications when used simultaneously.Regarding recovery time, when the dosage exceeds 3 μg/ kg, the recovery time does not always increase with the dosage; instead, it remains between 44 and 91 minutes. [61]Sin and colleagues assessed the impact of DEX on Postanesthesia Care Unit stay duration in their meta-analysis, revealing that the stay duration for the DEX group was only 0.69 (MD) minutes longer compared to the placebo group.Therefore, DEX does not delay recovery time. [63]onsidering the complexities of treating pediatric patients, we compared different routes of administration and found that the intranasal route yielded the best outcomes.This method delivers the drug directly to the mucosa, thereby avoiding hepatic first-pass metabolism and theoretically achieving plasma levels equivalent to those of an intravenous dose. [64]This approach is particularly suitable for patients who experience pre-event anxiety, separation anxiety from their parents, and exhibit a lack of cooperation.It is favored because it has no irritating odor, does not cause respiratory depression, and is easier to administer than oral and intravenous routes . [65,66]Apart from the traditional methods, the drug can also be administered using an atomizer.This method shows no significant difference in bioavailability, median onset time, and duration of sedation compared to the intranasal route and is easier for patients to accept. [61]In addition to the routes of delivery discussed previously, there are numerous other methods such as intramuscular, epidural, intrathecal, interfascial, perineural, and even peritonsillar routes. [7]hese are predominantly used during pediatric surgeries to reduce perioperative pain.However, we have not found articles linking these routes to delirium, and therefore, they are not discussed in this meta-analysis.

Shortcomings
Our meta-analysis clearly delineates between the concepts of delirium and agitation, though it does include certain studies that assess agitation using the PAED scale.Consequently, the precision of the data might be somewhat compromised.Additionally, in our comparison groups, we found only 1 article each for interventions such as chloral hydrate, melatonin, xenon, and physical methods.A similar scarcity of literature was noted for clonidine, dezocine, ondansetron, dexamethasone, ketamine, and esketamine.Due to various factors, these data sets demonstrated either no significant differences or lacked representativeness when compared with the DEX groups.As a result, these medications were not included in our meta-analysis.Moreover, our study is subject to several other limitations, including variability in population characteristics, small sample sizes within each subgroup, inconsistent dosages and regimens of DEX, diverse types of concomitant medications, and differences in primary outcomes.Regrettably, these constraints prevented a more detailed stratification of the articles in our analysis.

Conclusion
DEX offers significant advantages in preventing ED in pediatric anesthesia, especially in short-term anesthesia events.As an anesthesia adjuvant, it has minimal impact on the respiratory and cardiovascular systems, provides potential brain protection, and results in low rates of postoperative nausea and vomiting.Its various delivery methods make it suitable for use in busy pediatric settings.However, careful patient selection and dosage are necessary since DEX is used "off-label" in children.While there is potential for DEX to replace certain hypnotics, further research is needed to fully understand its benefits and limitations in pediatric care.

Figure 2 .
Figure 2. Risk of bias summary review authors' judgments about each risk of bias item for each included study.

Figure 3 .
Figure 3.Comparison of pediatric ED between DEX and all comparator groups.

Figure 4 .
Figure 4.The funnel plot of comparison of pediatric ED between DEX and all comparator groups.

Figure 5 .
Figure 5.Comparison of pediatric ED between DEX and saline groups.

Figure 6 .
Figure 6.Comparison of pediatric ED between DEX and midazolam groups.

Figure 7 .
Figure 7.Comparison of pediatric ED between DEX and propofol groups.

Figure 8 .
Figure 8.Comparison of pediatric ED between DEX and other groups.
8) types of other comparators; (9) infusion speed or dosage of DEX or other sedatives; (10) ways of drug delivery; (11) number of patients with ED following sedation or general anesthesia; and (12) other anesthetic medicines that may affect the results.
authors; (2) publication year; (3) number of the total participants in each study; (4) age range of all the participants; (5) country of publication; (6) procedures that the participants underwent; (7) time of DEX or other comparators administration; (

Table 1
The basic information of all included trials.

Table 2
Summary of findings table with GRADE assessment quality of evidence.

Table 3
The outcomes of subgroup analysis and recovery time between different dosages of DEX after events.